During the COVID-19 pandemic, Malaysia adopted heterologous vaccine booster strategies using BNT162b2 (Pfizer), CoronaVac (Sinovac) and ChAdOx1 nCoV-19 (AstraZeneca) due to vaccine shortages. However, longitudinal data on immune durability and breakthrough infections, especially in immunocompromised groups, remain limited. This study evaluates humoral response in healthy individuals after primary vaccine series and booster dose, and assesses long-term hybrid immunity up to two years post-booster in both healthy individuals and immunocompromised kidney transplant recipients (KTRs). BNT162b2 vaccine elicited a stronger anti-spike (anti-S) antibody response (3.0 log U/mL) compared to CoronaVac (1.6 log U/mL) at 3 months post-second dose. Anti-nucleocapsid (anti-N) antibody seroconversion was 50.3 % in CoronaVac recipients, suggesting limited humoral responses against N protein. Booster vaccination with homologous or heterologous mRNA-based regimens (BNT162b2/BNT162b2, ChAdOx1 nCoV-19/BNT162b2, and CoronaVac/BNT162b2) further enhanced anti-S antibody responses (3.6-3.7 log U/mL) for up to 6 months, whereas homologous CoronaVac/CoronaVac boosters yielded lower antibody levels (2.8 log U/mL). Breakthrough infections triggered a rapid rise in anti-N antibody, followed by a decline back to pre-infection levels within 3 months. In individuals infected two years after booster vaccination, T cell responses increased in healthy participants but declined in KTRs despite strong antibody responses, suggesting immunosuppressive therapy may impair T cell activation. These findings highlight the need for comprehensive immune assessments to guide preventive strategies, especially for immunocompromised populations.
